The integrity of the medial temporal lobe (MTL), which is composed of multiple interacting subregions, is critical for human memory function. Healthy aging appears to involve relatively minor alterations in some subregions of the MTL memory system, while Alzheimer's disease (AD) even at an early clinical stage arises from considerable abnormalities in multiple MTL subregions. Post-mortem studies imply that AD neuropathology accumulates sequentially, beginning in layer II cellular "islands" of the entorhinal cortex (ERC), disrupting the perforant pathway from ERC to hippocampus proper (HP), and ultimately affecting HP directly. Yet imaging techniques have not been available to study the fine structure of the MTL in living humans, so hypotheses related to this proposed sequential progression which has been inferred from cross-sectional analyses of post-mortem tissue have yet to be tested. We have recently made substantial progress developing ultra high-resolution MRI (uhrMRI) methods using a 3 Tesla system with a custom-built 32-channel head coil. We are now able to acquire in vivo structural MRI data of remarkable resolution (e.g., 0.30- 0.50mm, more than 3 times the resolution of typical research scans). Using these methods, we are beginning to visualize fine structural elements of MTL subregions, including the perforant pathway and layer II ERC cell islands. To our knowledge, these anatomical features have never been convincingly seen in living humans. We hypothesize that these uhrMRI methods can be used to visualize and quantify fine anatomical structural elements of MTL subregions, such as perforant pathway fibers and ERC layer II cell islands. The overall goal of this application is to further optimize uhrMRI methods to improve the visualization and quantification of MTL subregions, to validate these methods using ultra high-field (7 Tesla) ex vivo MRI of post-mortem tissue samples, and to begin to apply the in vivo methods to study changes in fine MTL structure with aging. Project Narrative: The identification and measurement of specific elements of the fine structure of the human medial temporal lobe would potentially be of great value for understanding normal human neuroanatomy as it relates to memory and aging, and how it is disrupted in the earliest stages of AD. The ultra high resolution MRI methods being developed to study the anatomy of this brain region in unprecedented detail will likely be applicable to other brain regions, which may be affected by other neurologic and psychiatric disorders. Thus, this work may have broad relevance to clinical neuroscience and the neurobiology of disease.